This invention relates to mass spectrometry and, particularly, to delivery of ions from a higher pressure ion source through a tubular interface to a mass analyzer operating at high vacuum.
Mass spectrometers have been shown to be particularly useful for analysis of liquid or gaseous samples, and mass spectrometry (xe2x80x9cMSxe2x80x9d) can be coupled with gas chromatography (xe2x80x9cGCxe2x80x9d) or liquid chromatography (xe2x80x9cLCxe2x80x9d) for analysis of substances having a wide range of polarities and molecular weights in samples obtained from a wide range of sources.
Mass spectrometers employing atmospheric pressure ionization (xe2x80x9cAPIxe2x80x9d) techniques can be particularly useful for obtaining mass spectra from liquid samples, and MS employing such ion sources are frequently used in conjunction with high performance liquid chromatography (xe2x80x9cHPLCxe2x80x9d), and combined HPLC/MS systems are commonly used for analysis of polar and ionic substances, including biomolecular species. In API techniques a liquid sample containing a mobile phase (e.g., solvent) and analytes is introduced into an ionization chamber and there converted to a charged dispersion or aerosol of fine droplets from which ions emerge as the liquid evaporates and the droplets shrink in size. The conversion of liquid to spray or aerosol can be accomplished by any of a variety of techniques. Evaporation of the liquid can be assisted, for example, by passing a flow of warm gas (xe2x80x9cdrying gasxe2x80x9d) through the cloud of droplets.
In mass spectrometry apparatus, an interface must be provided between a source of ions to be analyzed, which is typically at high-pressure (at or near atmospheric pressure in API sources), and the enclosure for the mass analyzer, which is typically at very low pressure. In one approach, a tube, having a bore usually of capillary dimension, serves as a conduit for the ions. One end of the capillary opens into the ionization chamber at about atmospheric pressure, and the other end of the capillary opens into the high vacuum chamber.
In some such apparatus the capillary interface is constructed of a dielectric material such as a glass and is provided at the ends with electrodes that are connected with sources of electrical potential. See, for example, U.S. Pat. No. 4,542,293. In conventional operation using a dielectric capillary interface the electrode at the upstream end of the capillary, in the ionization chamber, is held at a high magnitude electrical potential (typically in the range xe2x88x923000 V to xe2x88x926000 V for operation in a xe2x80x9cpositive ionxe2x80x9d mode; the polarity is reversed for operation in a xe2x80x9cnegative ionxe2x80x9d mode) and the electrode at the downstream end of the capillary, in the vacuum chamber, is held at a lower magnitude and oppositely charged electrical potential (typically in the range +50 V to +400 V for operation in a xe2x80x9cpositive ionxe2x80x9d mode). Ions are entrained in the flow of gas into the inlet end of the capillary from the higher pressure ion source chamber and carried with the gas, against the opposing electrical field, through the lumen of the capillary and out through the exit end of the capillary into the low pressure chamber downstream.
Various mass spectrometry apparatus employing a capillary interface between an atmospheric pressure ionization (xe2x80x9cAPIxe2x80x9d) ion source and the mass analyzer are described, for example, in U.S. Pat. No. 5,838,003 (electrospray ionization [xe2x80x9cESIxe2x80x9d]), U.S. Pat. No. 5,736,741 (ESI and atmospheric pressure chemical ionization [xe2x80x9cAPCIxe2x80x9d]), U.S. Pat. No. 5,726,447 (corona discharge ionization). These and any other patents and other publications referred to in this application are hereby incorporated herein in their entirety.
Considerable interest has developed, particularly in the pharmaceuticals and medical diagnostics industries, in employing mass spectrometry to analyze large numbers of samples that contain only a few analytes of interest. Typically the sources of the samples are biological fluids such as urine or blood. Samples from such sources contain significant quantities of substances that are not of interest in the analysis, and sample treatment for removal of these substances makes up a significant proportion of the cost of such analyses. Accordingly, some effort has been directed toward reducing the extent of sample treatment prior to introducing the sample to mass spectrometry apparatus. In one approach, tandem mass spectrometry (xe2x80x9cMS/MSxe2x80x9d) has been used in an effort to reduce the need for sample preparation for simple target compound analysis. MS/MS systems are significantly more costly than MS systems.
Techniques have been proposed for separating ions according to their mobility. In such ion mobility separation xe2x80x9cIMSxe2x80x9d techniques, an accelerating electrical potential is employed, to move ions against a countercurrent gas flow. In IMS, ions having higher mobility have higher drift velocities.
We have discovered that high pass ion filtration can be effected within a dielectric capillary interface between a higher pressure ionization chamber and the lower pressure environment of a mass analyzer in mass spectrometry apparatus, by application of electrical potentials to end electrodes and to at least one electrode associated with the dielectric capillary between the ends, to create an end-to-end electric field generally opposing the gas flow-assisted movement of ions from the upstream end to the downstream end, and to create a steeper voltage gradient along an upstream portion than along a downstream portion of the capillary. The voltage gradient along the steeper upstream portion of the capillary is sufficiently steep to cause ions having high mobility and having drift velocities below a lower limit to stall within the capillary. The respective potentials may be adjusted to increase the steepness of the upstream voltage gradient to increase the drift velocity lower limit.
The apparatus is inexpensive to construct and simple to operate. Because movement of ions from the higher pressure ionization chamber to the vacuum chamber is according to the invention assisted by gas flow through the capillary interface, ions having higher mobility have lower drift velocities. The high pass ion filter according to the invention can provide for removal of lower drift velocity ions from the population of ions that are delivered to the mass analyzer.
Accordingly, in one general aspect the invention features a conduit for transporting ions from a higher pressure ion source to a mass analyzer at high vacuum in mass spectrometry apparatus. The conduit includes a tube constructed of a dielectric material and defining a capillary bore extending from end to end and having an end electrode associated with each end and at least one additional electrode associated with the tube between the ends. The electrodes are connected to a source of electrical potential.
Electrodes are connected to xe2x80x9ca sourcexe2x80x9d of electrical potential, at that term is used herein, when they are electrically connected to separate voltage sources, and also when any two or more of them are electrically connected to a common single source that is provided with circuitry (e.g., resistive networks) that can be used to apply different voltages to the various electrodes.
In operation, electrical potentials are applied at the end electrodes and the additional electrode to generate an end-to-end electric field having a voltage gradient that is steeper along an upstream portion of the conduit than along a downstream portion of the conduit. Ions are carried by the flow of gas from the ion source through the conduit to the high vacuum environment of the mass analyzer, against the end-to-end electrical field gradient. In a positive ion mode the upstream end is kept more electronegative than the downstream end, while in a negative ion mode the upstream end is kept more electropositive than the downstream end. According to the invention, the steeper gradient in the more upstream portion of the conduit retards the downstream movement of ions having drift velocities below a lower limit, so that they are prevented from passing through and out from the conduit. As the retarding voltage gradient is made steeper, the lower limit increases.
In some embodiments at least two additional electrodes are associated with the dielectric tube between the ends.
In another general aspect the invention features a method for delivering ions from a higher-pressure ionization chamber to a mass analyzer operating at high vacuum. The method employs a conduit that includes a tube constructed of a dielectric material and defining a capillary bore from end to end and having an electrode associated with each end and at least one additional electrode associated with the tube between the ends. According to the method, electrical potentials are applied to the electrodes to generate an end-to-end electric field having a voltage gradient that is steeper along an upstream portion of the conduit than along a downstream portion of the conduit. The steeper voltage gradient upstream retards the downstream movement of ions having lower drift velocities and thereby reduces the flow of ions having lower drift velocities through and out from the conduit to the mass analyzer.
The expression xe2x80x9cdrift velocityxe2x80x9d, as that term is used in describing the invention herein, is the mean ion velocity within the capillary in a direction from the ionization chamber toward the vacuum chamber. According to the invention, because ion movement from the ionization chamber toward the vacuum chamber is assisted by gas flow (against an opposing electrical potential gradient), ions having higher mobilities have lower drift velocities.
The invention is especially useful in qualitative and quantitative treatment of complex samples in analytical schemes employing mass spectrometry (xe2x80x9cMSxe2x80x9d) coupled with liquid chromatography (xe2x80x9cLCxe2x80x9d), usually high performance liquid chromatography (xe2x80x9cHPLCxe2x80x9d). The invention can be especially useful where an atmospheric pressure ionization (xe2x80x9cAPIxe2x80x9d) technique, such as electrospray ionization (xe2x80x9cESIxe2x80x9d), or inductively coupled plasma ionization (xe2x80x9cICPxe2x80x9d) or atmospheric pressure chemical ionization (xe2x80x9cAPCIxe2x80x9d) is employed in LC/MS.